Summary Background Recombinant tissue plasminogen activator (rt-PA, alteplase) improved functional outcome in patients treated soon after acute ischaemic stroke in randomised trials, but licensing is ...restrictive and use varies widely. The IST-3 trial adds substantial new data. We therefore assessed all the evidence from randomised trials for rt-PA in acute ischaemic stroke in an updated systematic review and meta-analysis. Methods We searched for randomised trials of intravenous rt-PA versus control given within 6 h of onset of acute ischaemic stroke up to March 30, 2012. We estimated summary odds ratios (ORs) and 95% CI in the primary analysis for prespecified outcomes within 7 days and at the final follow-up of all patients treated up to 6 h after stroke. Findings In up to 12 trials (7012 patients), rt-PA given within 6 h of stroke significantly increased the odds of being alive and independent (modified Rankin Scale, mRS 0–2) at final follow-up (1611/3483 46·3% vs 1434/3404 42·1%, OR 1·17, 95% CI 1·06–1·29; p=0·001), absolute increase of 42 (19–66) per 1000 people treated, and favourable outcome (mRS 0–1) absolute increase of 55 (95% CI 33–77) per 1000. The benefit of rt-PA was greatest in patients treated within 3 h (mRS 0–2, 365/896 40·7% vs 280/883 31·7%, 1·53, 1·26–1·86, p<0·0001), absolute benefit of 90 (46–135) per 1000 people treated, and mRS 0–1 (283/896 31·6% vs 202/883 22·9%, 1·61, 1·30–1·90; p<0·0001), absolute benefit 87 (46–128) per 1000 treated. Numbers of deaths within 7 days were increased (250/2807 8·9% vs 174/2728 6·4%, 1·44, 1·18–1·76; p=0·0003), but by final follow-up the excess was no longer significant (679/3548 19·1% vs 640/3464 18·5%, 1·06, 0·94–1·20; p=0·33). Symptomatic intracranial haemorrhage (272/3548 7·7% vs 63/3463 1·8%, 3·72, 2·98–4·64; p<0·0001) accounted for most of the early excess deaths. Patients older than 80 years achieved similar benefit to those aged 80 years or younger, particularly when treated early. Interpretation The evidence indicates that intravenous rt-PA increased the proportion of patients who were alive with favourable outcome and alive and independent at final follow-up. The data strengthen previous evidence to treat patients as early as possible after acute ischaemic stroke, although some patients might benefit up to 6 h after stroke. Funding UK Medical Research Council, Stroke Association, University of Edinburgh, National Health Service Health Technology Assessment Programme, Swedish Heart-Lung Fund, AFA Insurances Stockholm (Arbetsmarknadens Partners Forsakringsbolag), Karolinska Institute, Marianne and Marcus Wallenberg Foundation, Research Council of Norway, Oslo University Hospital.
Postsynaptic densities (PSDs) are membrane semi-enclosed, submicron protein-enriched cellular compartments beneath postsynaptic membranes, which constantly exchange their components with bulk aqueous ...cytoplasm in synaptic spines. Formation and activity-dependent modulation of PSDs is considered as one of the most basic molecular events governing synaptic plasticity in the nervous system. In this study, we discover that SynGAP, one of the most abundant PSD proteins and a Ras/Rap GTPase activator, forms a homo-trimer and binds to multiple copies of PSD-95. Binding of SynGAP to PSD-95 induces phase separation of the complex, forming highly concentrated liquid-like droplets reminiscent of the PSD. The multivalent nature of the SynGAP/PSD-95 complex is critical for the phase separation to occur and for proper activity-dependent SynGAP dispersions from the PSD. In addition to revealing a dynamic anchoring mechanism of SynGAP at the PSD, our results also suggest a model for phase-transition-mediated formation of PSD.
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•SynGAP forms a coiled-coil trimer, and each binds to two molecules of PSD-95•SynGAP/PSD-95 complex undergoes liquid-liquid-phase separation•SynGAP/PSD-95 phase separation suggests a possible PSD formation mechanism•Phase-separation-mediated SynGAP PSD enrichment is correlated with synaptic activity
The interaction between two major components of postsynaptic densities induces phase separation of the newly formed complex into liquid-like droplets, suggesting a mechanism for the formation and activity-dependent modulation of synaptic complexes.
Almost 90 years have passed since Alexander Fleming discovered the antimicrobial activity of lysozyme, the first natural antibiotic isolated from our body. Since then, various types of molecules with ...antibiotic activity have been isolated from animals, insects, plants, and bacteria, and their use has revolutionized clinical medicine. So far, more than 1,200 types of peptides with antimicrobial activity have been isolated from various cells and tissues, and it appears that all living organisms use these antimicrobial peptides (AMPs) in their host defense. In the past decade, innate AMPs produced by mammals have been shown to be essential for the protection of skin and other organs. Their importance is because of their pleiotrophic functions to not only kill microbes but also control host physiological functions such as inflammation, angiogenesis, and wound healing. Recent advances in our understanding of the function of AMPs have associated their altered production with various human diseases such as psoriasis, atopic dermatitis, and rosacea. In this review, we summarize the history of AMP biology and provide an overview of recent research progress in this field.
Bidirectional synaptic plasticity occurs locally at individual synapses during long-term potentiation (LTP) or long-term depression (LTD), or globally during homeostatic scaling. LTP, LTD, and ...homeostatic scaling alter synaptic strength through changes in postsynaptic AMPA-type glutamate receptors (AMPARs), suggesting the existence of overlapping molecular mechanisms. Phosphorylation controls AMPAR trafficking during LTP/LTD. We addressed the role of AMPAR phosphorylation during homeostatic scaling. We observed bidirectional changes of the levels of phosphorylated GluA1 S845 during scaling, resulting from a loss of protein kinase A (PKA) from synapses during scaling down and enhanced activity of PKA in synapses during scaling up. Increased phosphorylation of S845 drove scaling up, while a knockin mutation of S845, or knockdown of the scaffold AKAP5, blocked scaling up. Finally, we show that AMPARs scale differentially based on their phosphorylation status at S845. These results show that rearrangement in PKA signaling controls AMPAR phosphorylation and surface targeting during homeostatic plasticity.
•Synaptic PKA activity and phosphorylation of AMPARs is altered during scaling•AKAP5 and GluA1 S845 are required for homeostatic scaling up•AMPA receptors scale differentially based on their phosphorylation state•The effect of neuromodulators and NMDAR activation are altered during scaling
The relationship between Hebbian plasticity and homeostatic scaling is not known. The PKA signaling pathway is a key regulator of homeostatic scaling and suggests how global plasticity can occur while being sensitive to local or prior signaling at individual synapses.
This review is intended to illuminate the emerging understanding of epigenetic modifications that regulate both adaptive and innate immunity in the skin. Host defense of the epidermis and dermis ...involves the interplay of many cell types to enable homeostasis; tolerance to the external environment; and appropriate response to transient microbial, chemical, and physical insults. To understand this process, the study of cutaneous immunology has focused on immune responses that reflect both adaptive learned and genetically programmed innate defense systems. However, recent advances have begun to reveal that epigenetic modifications of chromatin structure also have a major influence on the skin immune system. This deeper understanding of how enzymatic changes in chromatin structure can modify the skin immune system and may explain how environmental exposures during life, and the microbiome, lead to both short-term and long-term changes in cutaneous allergic and other inflammatory processes. Understanding the mechanisms responsible for alterations in gene and chromatin structure within skin immunocytes could provide key insights into the pathogenesis of inflammatory skin diseases that have thus far evaded understanding by dermatologists.
Automatic identification system (AIS) is becoming increasingly popular with marine vessels providing accessible, up-to-date information on vessel activity in the marine environment. Although AIS has ...been utilised in several different fields to address specific questions, no published work has outlined the potential of AIS as a tool for a wide range of industries and users of the marine environment such as spatial planning, developments, and local marine industries (e.g. fisheries). This work demonstrates a procedure for processing, analysing, and visualisation of AIS data with example outputs and their potential uses. Over 730000 data points of AIS information for 2013 from around Shetland were processed, analysed, and mapped. Tools used included density mapping, vessel tracks, interpolations of vessel dimensions, and ship type analysis. The dataset was broken down by sector into meaningful and usable data packets which could also be analysed over time. Density mapping, derived from both point and vessel track data, proved highly informative but were unable to address all aspects of the data. Vessel tracks showed variation in vessel routes, especially around island groups. Additional uses of AIS data were addressed and included risk mapping for invasive non-native species, fisheries, and general statistics. Temporal variation of vessel activity was also discussed.
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•Creation and maintenance of a vessel database was the key to fast processing.•Density mapping provided an excellent overview of vessel activity.•Vessel tracks defined up-to-date vessel routes.•Large temporal variations in vessel activity were noted for 2013.•Interpolations provided spatial information on vessel dimensions and speed.
Summary Cryptosporidium spp are well recognised as causes of diarrhoeal disease during waterborne epidemics and in immunocompromised hosts. Studies have also drawn attention to an underestimated ...global burden and suggest major gaps in optimum diagnosis, treatment, and immunisation. Cryptosporidiosis is increasingly identified as an important cause of morbidity and mortality worldwide. Studies in low-resource settings and high-income countries have confirmed the importance of cryptosporidium as a cause of diarrhoea and childhood malnutrition. Diagnostic tests for cryptosporidium infection are suboptimum, necessitating specialised tests that are often insensitive. Antigen-detection and PCR improve sensitivity, and multiplexed antigen detection and molecular assays are underused. Therapy has some effect in healthy hosts and no proven efficacy in patients with AIDS. Use of cryptosporidium genomes has helped to identify promising therapeutic targets, and drugs are in development, but methods to assess the efficacy in vitro and in animals are not well standardised. Partial immunity after exposure suggests the potential for successful vaccines, and several are in development; however, surrogates of protection are not well defined. Improved methods for propagation and genetic manipulation of the organism would be significant advances.
Magnetic resonance elastography (MRE) is an imaging technique for noninvasively and quantitatively assessing tissue stiffness, akin to palpation. MRE is further able assess the mechanical properties ...of tissues that cannot be reached by hand including the brain. The technique is a three-step process beginning with the introduction of shear waves into the tissue of interest by applying an external vibration. Next, the resulting motion is imaged using a phase-contrast MR pulse sequence with motion encoding gradients that are synchronized to the vibration. Finally, the measured displacement images are mathematically inverted to compute a map of the estimated stiffness. In the brain, the technique has demonstrated strong test-retest repeatability with typical errors of 1% for measuring global stiffness, 2% for measuring stiffness in the lobes of the brain, and 3–7% for measuring stiffness in subcortical gray matter. In healthy volunteers, multiple studies have confirmed that stiffness decreases with age, while more recent studies have demonstrated a strong relationship between viscoelasticity and behavioral performance. Furthermore, several studies have demonstrated the sensitivity of brain stiffness to neurodegeneration, as stiffness has been shown to decrease in multiple sclerosis and in several forms of dementia. Moreover, the spatial pattern of stiffness changes varies among these different classes of dementia. Finally, MRE is a promising tool for the preoperative assessment of intracranial tumors, as it can measure both tumor consistency and adherence to surrounding tissues. These factors are important predictors of surgical difficulty. In brief, MRE demonstrates potential value in a number of neurological diseases. However, significant opportunity remains to further refine the technique and better understand the underlying physiology.
•Magnetic resonance elastography (MRE) noninvasively measures tissue stiffness.•MRE can reliably measure global and regional stiffness in the brain in vivo.•Brain stiffness is sensitive to physiological and pathological processes.•Intracranial MRE can be used for preoperative assessment of tumors.•Further work is needed to refine technique and better understand biological basis.
Chronic pain can lead to anxiety and anxiety can enhance the sensation of pain. Unfortunately, little is known about the synaptic mechanisms that mediate these re-enforcing interactions. Here we ...characterized two forms of long-term potentiation (LTP) in the anterior cingulate cortex (ACC); a presynaptic form (pre-LTP) that requires kainate receptors and a postsynaptic form (post-LTP) that requires N-methyl-D-aspartate receptors. Pre-LTP also involves adenylyl cyclase and protein kinase A and is expressed via a mechanism involving hyperpolarization-activated cyclic nucleotide-gated (HCN) channels. Interestingly, chronic pain and anxiety both result in selective occlusion of pre-LTP. Significantly, microinjection of the HCN blocker ZD7288 into the ACC in vivo produces both anxiolytic and analgesic effects. Our results provide a mechanism by which two forms of LTP in the ACC may converge to mediate the interaction between anxiety and chronic pain.
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► Carbon catalyst was prepared by glucose hydrothermal carbonization. ► The carbon material contains –SO3H, –COOH, and phenolic –OH groups. ► The solid catalyst exhibits high ...catalytic activity for cellulose hydrolysis in ionic liquid. ► A reducing sugar yield of 72.7% can be obtained at 110°C for 240min reaction time. ► The catalyst can be recycled.
A sulfonated carbon material was prepared by incomplete hydrothermal carbonization of glucose followed by sulfonation. The carbon material contained –SO3H, –COOH, and phenolic –OH groups, and exhibited high catalytic performance for the hydrolysis of cellulose. A total reducing sugar (TRS) yield of 72.7% was obtained in ionic liquid 1-butyl-3-methyl imidazolium chloride at 110°C in 240min reaction time. The effect of water on the hydrolysis of cellulose in the catalytic system was studied. A water content of less than 2% in the ionic liquid promoted the formation of TRS, whereas a water content of greater than 2% lead to a decrease in TRS. The sulfonated carbon material catalyst was demonstrated to be stable for five cycles with minimal loss in catalytic activity. The use of an ionic liquid with functionalized carbon catalyst derived from glucose provides a green and efficient process for cellulose conversion.
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